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J. Biol. Chem., Vol. 281, Issue 36, 26298-26307, September 8, 2006

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Antiinflammatory and Immunosuppressive Activity of Sialostatin L, a Salivary Cystatin from the Tick Ixodes scapularis^*

Michalis Kotsyfakis, Anderson Sá-Nunes, Ivo M. B. Francischetti, Thomas N. Mather, John F. Andersen, and José M. C. Ribeiro¹

From the Vector Biology Section, Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852 and the Center for Vector-Borne Disease, University of Rhode Island, Kingston, Rhode Island 02881

Here we report the ability of the tick Ixodes scapularis, the main vector of Lyme disease in the United States, to actively and specifically affect the host proteolytic activity in the sites of infestation through the release of a cystatin constituent of its saliva. The cystatin presence in the saliva was verified both biochemically and immunologically. We named the protein sialostatin L because of its inhibitory action against cathepsin L. We also show that the proteases it targets, although limited in number, have a prominent role in the proteolytic cascades that take place in the extracellular and intracellular environment. As a result, sialostatin L displays an antiinflammatory role and inhibits proliferation of cytotoxic T lymphocytes. Beyond unraveling another component accounting for the properties of tick saliva, contributing to feeding success and pathogen transmission, we describe a novel tool for studying the role of papain-like proteases in diverse biologic phenomena and a protein with numerous potential pharmaceutical applications.

Received for publication, December 6, 2005 , and in revised form, June 12, 2006.

^* This work was supported by the Division of Intramural Research, NIAID, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, 12735 Twinbrook Parkway, Rm. 2E-32, Rockville, MD 20852. Tel.: 301-496-9389; Fax: 301-480-2571; E-mail: jribeiro{at}niaid.nih.gov.

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